Parkinson's: Modified protein works like a drug

New research, published in the journal Molecular Neurobiology, offers a promising new strategy for restoring functional levels of dopamine in the brain: changing a naturally occurring protein so that it can enter brain cells and be used as a drug.

Parkinson's disease, a progressively debilitating neurological condition affecting about 1 million people in the United States, is caused by the loss of dopamine-producing neurons.

Currently, researchers are seeking strategies for either replacing or restoring their functionality, or raising the levels of dopamine, which is a neurotransmitter crucial for controlling movement.

Most recently, for instance, researchers have used light to control a drug that blocks certain receptors in the brain. Blocking these receptors increases dopamine.

Other studies have used vitamin B-3 in order to stop the death of dopamine-producing neurons or suggested that increasing dopamine only in short bursts, rather than constantly, can help control movement.

Now, a new study takes another approach. Building on previous research that singled out a protein called Nurr1 as a promising drug target for Parkinson's, an international team of scientists has altered the protein in a way that allows it to enter brain cells.

In this form, the naturally occurring protein can help dopaminergic neurons survive, explain the scientists in their paper, the first author of which was Dennis Paliga, from the Molecular Neurobiochemistry work group at the Ruhr-Universität Bochum in Germany.

Modifying the Nurr1 protein

Paliga and team explain that Nurr1 is a transcription factor that plays a vital role in the development and maintenance of dopamine-producing neurons in a brain area called the substantia nigra.

Previous studies referenced by the authors have found a deficiency of the Nurr1 protein in cases of Parkinson's disease, leading to the belief that supplementing Nurr1 levels might be a good therapeutic strategy.

Transcription factors help cells develop by binding to the DNA in the nucleus and "deciding" which genes are decoded so that they form proteins.

However, in its natural form, Nurr1 cannot enter cells from the outside. So, Paliga and team looked for ways to give it a "signal boost" that would prompt it to do so.

Attaching a protein fragment created from the bacterium Bacillus anthracis to Nurr1 proved to be the "boost" that the researchers were looking for.

"The fragment of bacterial protein that we used does not trigger diseases," states corresponding author Rolf Heumann. "[I]t merely contains the command to transport something into the cell," he adds.

When the modified protein enters the cell, it detaches itself from the bacterial protein fragment, free to target the genes that set in motion the production of dopamine.

How altered Nurr1 stops neurodegeneration

More specifically, further laboratory tests by Paliga and colleagues revealed that administering the modified version of Nurr1 increased levels of an enzyme that is key for dopamine synthesis, a process often disrupted in Parkinson's.

The enzyme is called tyrosine hydroxylase. Cell cultures have revealed that Nurr1-treated cells produced more of this enzyme than their untreated counterparts. However, treating the cells with the protein also decreased the production of another protein known as Nur77, which regulates cell death.

Finally, the researchers tested the effect of Nurr1 on dopamine-producing neurons that had been treated with a neurotoxin to simulate the effects of Parkinson's disease. The modified Nurr1 stopped the degeneration of the neurons.

"These findings," explain the study authors, "may have relevance for the nuclear delivery of Nurr1 transcription factor in the context of protein-based treatments in Parkinson's disease."

Study co-author Sebastian Neumann — who is affiliated with the Molecular Neurobiochemistry work group — also comments on the findings.

"We hope we can thus pave the way for new Parkinson's therapy [...] Still, our Nurr1 fusion protein can merely kick off the development of a new approach."

Sebastian Neumann

"Many steps still remain to be taken in order to clarify if the modified protein specifically reaches the right cells in the brain and how it could be applied," Neumann concludes.